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Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors

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Summary

Temozolomide (TMZ) generates DNA adducts that are repaired by direct DNA and base excision repair mechanisms. Methoxyamine (MX, TRC-102) potentiates TMZ activity by binding to apurinic and apyrimidinic (AP) sites after removal of N3-methyladenine and N7-methylguanine, inhibiting site recognition of AP endonuclease. We conducted a phase I trial to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of intravenous MX when given with oral TMZ. Patients with advanced solid tumors and progression on standard treatment were enrolled to a standard 3 + 3 dose escalation trial assessing escalating doses of TMZ and MX. Tumor response was assessed per RECIST and adverse events (AEs) by CTCAEv3. Pharmacokinetics (PK) of MX and COMET assays on peripheral blood mononuclear cells were performed. 38 patients were enrolled—median age 59.5 years (38–76), mean number of cycles 2.9 [1–13]. No DLTs were observed. Cycle 1 grade 3 AEs included fatigue, lymphopenia, anemia, INR, leukopenia, neutropenia, allergic reaction, constipation, psychosis and paranoia. Cycle 2–13 grade 4 AEs included thrombocytopenia and confusion. A partial response was seen in 1 patient with a pancreatic neuroendocrine tumor (PNET) and six additional patients, each with different tumor types, demonstrated prolonged stable disease. MX PK was linear with dose and was not affected by concomitant TMZ. TMZ 200 mg/m2 daily × 5 may be safely administered with MX 150 mg/m2 intravenously once on day 1 with minimal toxicity. Further studies assessing this drug combination in select tumor types where temozolomide has activity may be warranted.

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Funding

This project was supported NCI grants R21 CA126149 and 5R01 CA86357 and by the Case Comprehensive Cancer Center (CCCC) (P30CA043703), the Translational Research and Pharmacology Core Facility of the CCCC, the UPMC Hillman Cancer Center Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and the following awards—P30CA47904, 5K12CA076917–17.

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Authors and Affiliations

  1. Case Comprehensive Cancer Center, Case Western Reserve University, University Hospitals Seidman Cancer Center, 11100 Euclid Avenue, Lakeside 1200, Cleveland, OH, 44106, USA

    Jennifer R. Eads, Smitha S. Krishnamurthi, Joel Saltzman, Joseph A. Bokar, Joseph Gibbons, Henry Koon, Lisa Rogers, John Riendeau, Stanton L. Gerson & Afshin Dowlati

  2. St. Joseph’s Hospital and Medical Center, University of Arizona Comprehensive Cancer Center, University of Arizona, Phoenix, AZ, USA

    Panos Savvides

  3. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Neal J. Meropol, John J. Pink & Pingfu Fu

  4. Flatiron Health, New York, NY, USA

    Neal J. Meropol

  5. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

    Neelesh Sharma

  6. Case Comprehensive Cancer Center, Cleveland State University, Cleveland, OH, USA

    Yan Xu

  7. UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    Jan H. Beumer

Authors
  1. Jennifer R. Eads
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Corresponding author

Correspondence to Afshin Dowlati.

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Conflict of interest

Jennifer Eads reports no conflict of interest.

Smitha S. Krishnamurthi reports no conflict of interest.

Joel Saltzman reports no conflict of interest.

Joseph A. Bokar reports no conflict of interest.

Panos Savvides reports no conflict of interest.

Neal J. Meropol is an employee of Flatiron Health, Inc., an independent subsidiary of the Roche Group. NJM holds equity interest in Flatiron Health and Roche.

Joseph Gibbons reports no conflict of interest.

Henry Koon is an employee of Bristol Myers Squibb.

Neelesh Sharma is an employee of Novartis.

Lisa Rogers reports no conflict of interest.

John J. Pink reports no conflict of interest.

Yan Xu reports no conflict of interest.

Jan H. Beumer reports no conflict of interest.

John Riendeau reports no conflict of interest.

Pingfu Fu reports no conflict of interest.

Stanton L. Gerson is inventor of a patent on methoxyamine. The intellectual property on methoxyamine has been licensed by Case Western Reserve University to Tracon Pharmaceuticals, Inc., and Dr. Gerson owns stock in, and is a paid consultant for Tracon Pharmaceuticals, Inc.

Afshin Dowlati reports research support (to institution) by Ipsen, Tesaro, Takeda, Astra Zeneca, Bayer, Eli-Lilly, Abbvie, Seattle Genetics, Bristol Myers-Squibb, Regeneron, Amgen, Symphogen. Dr. Dowlati reports advisory role for Seattle Genetics, Takeda, Abbvie, Bristol Myers-Squibb and Astra Zeneca.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Table 4 Dose escalation strategy
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Eads, J.R., Krishnamurthi, S.S., Saltzman, J. et al. Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors. Invest New Drugs 39, 142–151 (2021). https://doi.org/10.1007/s10637-020-00962-x

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